DESCRIPTION (From the Applicant's Abstract): Uveal melanoma is the most common and malignant intraocular tumor in adults. Metastases appear in 19 percent to 35 percent of patients within 5 years of diagnosis of uveal melanoma. The liver is the primary organ for the development of metastases and up to 95 percent of the patients who die from uveal melanoma, have liver metastases. Although the treatment of primary uveal melanoma has improved substantially over the past two decades, there have been no significant advances in the management of metastases and as such, the five year survival time for uveal melanoma patients has not changed in over 25 years. Regretably, there still remains no effective treatment for uveal melanoma metastases. This Research Plan will address three specific aims relating to the immunobiology and therapy of liver metastases, the leading cause of morbidity and mortality in uveal melanoma patients. The proposed studies consider three hypotheses. The first hypothesis proposes that a component of the innate immune system, the natural killer (NK) cell repertoire, is instrumental in controlling metastases arising from intraocular melanomas. A corollary of this hypothesis is that successful uveal melanoma metastases employ a variety of escape mechanisms to thwart NK cell-mediated immune surveillance. The second hypothesis predicts that therapeutic strategies that stimulate NK activity will overcome the NK escape mechanisms of uveal melanomas and will culminate in reduced liver metastases and improved host survival. The third hypothesis predicts that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be effectively used to treat uveal melanoma liver metastases. The specific aims for this project are: 1) Evaluate and characterize NK cell escape mechanisms employed by uveal melanoma cells; 2) evaluate NK cell-based immunotherapy; and 3) evaluate tumor necrosis factor-related-apoptosis inducing ligand (TRAIL)based therapy. These studies will utilize a well-characterized mouse model that recapitulates the human counterpart. The long rang goal of this project is to design, develop, and evaluate novel immunotherapeutic modalities for the prevention and treatment of uveal melanoma metastases.